The present invention is directed to the synthesis of a series of radioligands, labeled with a positron emitting radionuclide, fluorine-18, which are suitable for dynamic studies in humans using positron emission transaxial tomography. One of the preferred radio-labeled ligands of this series, no-carrier-added (NCA) N-(3-[.sup.18 F]fluoropropyl)spiroperidol exhibits extremely high affinity for dopamine receptors and provides enhanced uptake and retention in the brain concomitant with reduced radiation burden. These characteristics all combine to make NCA N-(3-[.sup.18 F]fluoropropyl)spiroperidol a radioligand that is well suited for use in mapping dopamine receptors in normal and diseased states in the living brain.
Recent advances in the study of neuropsychiatric diseases link manifestations of a disease to chemical changes in the brain. For example, the dopamine neurotransmitter has been linked with both Parkinson's disease and schizophrenia as a source for altered synaptic transmission at the biochemical level.
The development of positron emission transaxial tomography (PET) has now made it possible to study the dopamine receptors in a living human brain. Radioligands labeled with positron emitting radionuclides permit quantitative studies based on annihilation radiation produced during positron emission. The technique consists of intravenous injection of a radioligand or radiopharmaceutical and subsequent imaging of the distribution of the radioactive label based on detection of the annihilation radiation produced during positron emission.
Radioligands which have proved useful for such studies are those with a high in vivo affinity for the dopamine receptors. To date, one of the most promising such radioligand has been [.sup.18 F]-N-methylspiroperidol whose synthesis and use is described by Shiue, et al., Journal of Nuclear Medicine, 27: 226-234 (1986) Arnett et al., Life Science, 36: 1359-1366 (1985); and Arnett et al., Journal of Nuclear Medicine, 27: 1878-1882 (1986). However, there are several significant drawbacks to the use of this radioligand. The synthesis of [.sup.18 F]-N-methylspiroperidol is a multi-step process, the yields are not optimum, and the starting materials used to prepare this tracer, namely cyclopropyl-p-nitrophenyl ketone and 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]deca-4-one, are not commercially available materials and thus have to be synthesized independently prior to synthesis of the radioligand.
In the present invention, no-carrier-added (NCA) N-(3-[.sup.18 F]fluoropropyl)spiroperidol, a new radioligand which exhibits similar uptake into the brain's dopamine receptor rich areas as [.sup.18 F]-N-methylspiroperidol and is thus equally valuable in studying dopamine receptors in humans using PET is prepared by the N-alkylation of spiroperidol. Both spiroperidol and the alkylating agent precursor prior to [.sup.18]labeling are commercially available materials thus greatly simplifying the synthesis of the valuable radioligand and yielding the tracer in radiochemical yields greater than 20% at high specific activity. The biodistribution and kinetic distribution of N-(3-[.sup.18 F]fluoropropyl)spiroperidol are appropriate for mapping dopamine receptors and the striatal accumulation of radioactivity was blocked stereoselectively by (+)-butaclamol. The baboon blood total plasma radioactivity clearance was rapid and the analysis of the metabolic stability of this novel radioligand in mouse brain for one hour indicated that it is very stable to metabolic transformation in the central nervous system. N-(3-[.sup.18 F]fluoropropyl)-spiroperidol has the characteristics to be a useful radioligand for PET studies of the dopamine receptors in humans.
In a further aspect of the present invention, a series of [.sup.18 F]-N-fluoroalkylspiroperidols similar to N-(3-[.sup.18 F]fluoropropyl)spiroperidol are prepared for use in PET studies.
In a still further aspect of the present invention, [.sup.18 F]fluoroalkyl halides are prepared and used in the synthesis of the novel [.sup.18 F]-N-fluoroalkylspiroperidols.